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Primary Sjögren syndrome (pSS) is a prototypical autoimmune disease. The involvement of B cells in the pathogenesis of pSS has long been suspected on the basis of clinical observations that include the presence of serum autoantibodies, hypergammaglobulinaemia, increased levels of free light chains and increased risk of B cell lymphoma. Moreover, the composition of the B cell subset is altered in pSS. In this Review, we discuss the mechanisms that support the increased activation of B cells in pSS, including genetic and epigenetic factors and environmental triggers that promote B cell activation via the innate immune system. B cell activating factor (BAFF, also known as TNF ligand superfamily member 13B) is at the crossroads of this process. An important role also exists for the target tissue (exocrine glands, namely the salivary and lachrymal glands), which promotes local B cell activation. This continuous stimulation of B cells is the main driver of lymphomatous escape. Identification of the multiple steps that support B cell activation has led to the development of promising targeted therapies that will hopefully lead to the development of an efficient therapeutic strategy for pSS.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics.Advances in understanding the pathogenic mechanisms of primary Sjögren syndrome (pSS) and the development of new outcome measures are aiding drug development for this disease. This Review describes current treatments and highlights promising candidates for future therapies for pSS.

In the past decade, knowledge of the pathogenesis of primary Sjögren's syndrome and the lymphomagenesis associated with this disease has advanced considerably. This Review summarizes our current understanding of these processes, highlighting the importance of crosstalk between the innate and adaptive immune systems. Primary Sjögren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications. Key Points Environmental triggers promote activation of the innate immune system and the production of interferons (IFNs), which, in susceptible individuals, represent the first stages of primary Sjögren's syndrome (pSS) pathogenesis B-cell-activating factor is induced by type I and type II IFNs and has a key role in activating autoreactive B cells; other cytokines such IL-21 could also be important for this process Continuous B-cell activation as a result of the autoimmune response and subtle deficiencies in the control of nuclear factor κB activation might underlie increased lymphomagenesis associated with pSS IL-12 is a central cytokine in pSS pathogenesis, promoting activation of the type II IFN system via both the innate (natural killer cells) and the adaptive (type 1 T-helper cells) immune systems Epithelial cells are major players in pSS pathogenesis, not only as targets of disease, but also as drivers of the disease process that promote overactivation of the immune system Many similarities exist between systemic lupus erythematosus and pSS pathogenesis; the main pathogenetic difference is the mucosa tropism of pSS, the basis for which remains unknown

Our objective was to define the effect of JAK inhibitor (JAKinib) withdrawal on JAK/STAT biochemical response in the context of systemic rheumatic diseases. We tested Type I (bind kinase active conformation) and Type II (bind kinase inactive conformation) JAKinibs in vitro using mesenchymal stromal cells (MSCs) and human umbilical vein endothelial cells (HUVECs). We translated our findings in vivo studying NK cells from rheumatoid arthritis (RA) patients treated with Type I JAKinibs or methotrexate. Type I JAKinibs (ruxolitinib and baricitinib) increased phosphoJAK1 (pJAK1) and pJAK2 of IFNγ-stimulated MSCs and HUVECs in a time- and dose- dependent manner, with effect peaking after 24 hours. As expected, pSTAT1 was completely suppressed by JAKinibs. We found a marked and rapid increase of pSTATs upon discontinuation of Type I JAKinibs, that occurred to a lesser extent after Type II JAKinib withdrawal. Type I JAKinib withdrawal increased interferon and urokinase expression when compared to Type II JAKinib withdrawal. We found NK cells from RA patients taking Type I JAKinibs had a pro-inflammatory profile after JAKinib withdrawal compared to patients on methotrexate. Type I JAKinibs paradoxically accumulate functionally defective pJAK. Upon withdrawal, the primed pJAKs are de-repressed and initiate a pSTAT signaling cascade, resulting in high interferon and urokinase. Type II JAKinibs do not cause pJAK accumulation, pSTAT cascade, and subsequent pro-inflammatory transcripts. The resultant cytokines and proteins produced from this cascade might explain adverse cardiac outcomes. Thus, JAKinib withdrawal is a possible mechanism contributing to the major adverse cardiac events described with JAKinib therapy.

The first description of the involvement of interferons (IFN) in systemic autoimmune diseases (AID) dates back more than 40 years.1 IFNs play a crucial role in numbers of immunological pathways involve in AID, such as induction of dendritic cell (mDC), MHC expression, cytokines like BAFF, IL-2, IL-7. The aim of this editorial is not to discuss all these mechanisms linking IFNs to autoimmunity but to discuss the origin and signification of what is called ‘the IFN signature’ and how measuring it. The diseases in which this signature plays a prominent role are systemic erythematosus lupus (SLE), Sjögren’s syndrome (SS),2 3 inflammatory myositis4 and scleroderma.5 The study of this IFN signature is still attracting the interest of research teams around the world, and for good reason: the advent of IFN-targeted therapies could revolutionise the outcome of patients with IFN-mediated diseases. However, behind this so-called IFN signature, there are still many grey areas: what type(s) of IFNs are we talking about? Who are the producers of IFNs? What is the origin of this IFN signature? What tools for assessing the IFN signature? Several techniques have been developed including IFN-inducible gene signatures; IFN-inducible proteins such as MxA, Galectin 9, Siglec1, IP-10; reporter system with WISH cells; dosage of the different subtypes of circulating IFNs. And finally, what are the consequences of this IFN signature in clinical practice, both in the classification of patients with the aim of achieving personalised medicine, and in the management of treatments, particularly at a time when therapies targeting IFNs are being developed?

To analyze the clinical and immunological characteristics at enrollment in a large prospective cohort of patients with primary Sjögren's syndrome (pSS) and to investigate the association between serum BAFF, beta2-microglobulin and free light chains of immunoglobulins and systemic disease activity at enrollment. Three hundred and ninety five patients with pSS according to American-European Consensus Criteria were included from fifteen centers of Rheumatology and Internal Medicine in the \"Assessment of Systemic Signs and Evolution of Sjögren's Syndrome\" (ASSESS) 5-year prospective cohort. At enrollment, serum markers were assessed as well as activity of the disease measured with the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI). Patient median age was 58 (25(th)-75(th): 51-67) and median disease duration was 5 (2-9) years. Median ESSDAI at enrollment was 2 (0-7) with 30.9% of patients having features of systemic involvement. Patients with elevated BAFF, beta2-microglobulin and kappa, lambda FLCS had higher ESSDAI scores at enrollment (4 [2]-[11] vs 2 [0-7], P = 0.03; 4 [1]-[11] vs 2 [0-7], P< 0.0001); 4 [2]-[10] vs 2 [0-6.6], P< 0.0001 and 4 [2-8.2] vs 2 [0-7.0], P = 0.02, respectively). In multivariate analysis, increased beta2-microglobulin, kappa and lambda FLCs were associated with a higher ESSDAI score. Median BAFF and beta2-microglobulin were higher in the 16 patients with history of lymphoma (1173.3(873.1-3665.5) vs 898.9 (715.9-1187.2) pg/ml, P = 0.01 and 2.6 (2.2-2.9) vs 2.1 (1.8-2.6) mg/l, P = 0.04, respectively). In pSS, higher levels of beta2-microglobulin and free light chains of immunoglobulins are associated with increased systemic disease activity.

ObjectiveAnti-SS-B antibodies are often associated with anti-SS-A in Sjögren’s disease. Compared to anti-SS-A antibody positivity, the significance of the immunological profile anti-SS-B positive/anti-SS-A negative remains controversial. We aimed to evaluate the prevalence and diagnostic significance of isolated anti-SS-B antibodies.MethodsWe conducted a retrospective study across three hospitals of the Assistance Publique—Hôpitaux de Paris. Patients with anti-SS-B positivity were identified using ELISA, addressable laser beam immunoassay (ALBIA) and immunodot assays. They were retained if anti-SS-B was positive in two techniques and anti-SS-A was absent. Clinical, biological and immunological data were extracted and presented in a descriptive analysis.ResultsA total of 80 540 requests for anti-SS-B antibody testing were carried out over a period of 7.9 years. Anti-SS-B positivity was found in 1693 patients. Among them, 335 (19.8%) patients had isolated anti-SS-B in ELISA/ALBIA. Immunodot was performed in 186 of them and confirmed anti-SS-B positivity in 61 patients (3.6% of anti-SS-B positivity). 24 patients (39.3%) presented with a history of various autoimmune or autoinflammatory diseases and only 6 were diagnosed with a new connective tissue disease. After a median follow-up of 26 months, only two new diagnoses were made.ConclusionAnti-SS-B without anti-SS-A is exceedingly rare when accurately identified by a rigorous immunological approach. The initial anti-SS-B positivity does not correlate with a specific condition, both at the time of initial identification and after a 26-month follow-up period. This supports the fact that isolated anti-SS-B has no diagnostic or prognostic value.

BackgroundProgrammed cell death protein 1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) are immune checkpoints expressed on T cells. Despite recent development of PD-1 agonists in rheumatoid arthritis (RA), little is known about PD-1 and TIGIT coexpression in RA and other immune-mediated inflammatory diseases (IMIDs). This study quantified PD-1 and TIGIT expression in CD4 and CD8 T cells in patients with IMID and examined associations with disease characteristics and anti-tumour necrosis factor (TNF) response.MethodsBiologics-naïve patients with RA and spondyloarthritis (AS) were followed prospectively to assess anti-TNF response at 12 months. Sjögren’s disease (SjD) patients and healthy volunteers (HV) were also included at baseline. PD-1 and TIGIT expression on CD4 and CD8 T cells was analysed by flow cytometry at baseline and after 3 months of anti-TNF treatment. Plasma cytokines were quantified using the Meso Scale Discovery assay.Results67 patients were included. Median CD8+PD-1+TIGIT+ levels were higher in RA (24%) and SjD (23.2%) than in HV (18.8%) and AS (16.2%). CD4+PD-1+TIGIT+ were positively correlated with circulating immunoglobulin G (r=0.698, p<0.001), interferon gamma (r=0.635, p=0.017) and IP-10 (r=0.612 p=0.005) levels in patients with SjD. Baseline CD4+PD-1+TIGIT+ levels were higher in future anti-TNF responders (9.9%) compared with non-responders (6.1%, p=0.003). Both CD4+PD-1+TIGIT+ and CD8+PD-1+TIGIT+ cells increased after 3 months of anti-TNF treatment in RA and AS.ConclusionCD8+PD-1+TIGIT+ T-cell expression is elevated in SjD and RA compared with HV and AS. CD4+PD-1+TIGIT+ levels are higher in future anti-TNF responders compared with non-responders and rise after treatment in patients with RA and AS. Further studies should clarify the functional role of CD4+PD-1+TIGIT+ cells in IMIDs.